KR19990080447A - Stereoselective synthesis of oxazoline derivatives equivalent to beta-amino-alpha-hydroxy acids - Google Patents

Abstract

The present invention is a method for synthesizing an oxazoline derivative equivalent to β-amino-α-hydroxy acid from α-amino acid. Synthesis of intermediate compounds that can be used as substrates for palladium (0) catalysts using α-amino acids as starting materials, followed by synthesis of oxazoline derivatives using intramolecular cyclization using palladium (0) catalysts Unlike the method, it can be applied to all α-amino acids, and in synthesizing the taxol side chain, it is characterized by superior stereoselectivity than the conventional method.

Description

Stereoselective synthesis of oxazoline derivatives equivalent to beta-amino-alpha-hydroxy acids

The present invention relates to a stereoselective synthesis method of oxazoline derivatives equivalent to β-amino-α-hydroxy acids. More particularly, the present invention relates to a method for synthesizing an oxazoline derivative having the structure of the following general formula (I).

(Formula I)

In the above formula

R is phenyl, benzyl, methyl, ethyl, isopropyl, isobutyl, cyclohexyl or cyclohexylmethyl.

β-amino-α-hydroxy acids are important constituents of HIV protease inhibitors or other potent compounds. Taxol having a structure of the following general formula (A) has been found to be an effective anticancer agent, and in order to exhibit the anticancer effect of Taxol, 3- (N-benzoylamino) -2-hydroxy-3-phenyl at the C-13 position Propionic acid is known to be essential.

(Formula A)

Such natural taxanes have been found in plants and have been isolated from plants. However, since the taxane is present in a relatively small amount in plants, the anticancer effect is excellent, but it is difficult to secure a large amount of such compounds. However, Bacatin III of formula (B), which is the parent of Taxol, can be obtained in a larger amount than Taxol from plants, and thus it is possible to synthesize Taxol through semisynthesis. Therefore, it is very important to develop a stereoselective method for synthesizing β-amino-α-hydroxy acids such as side chains, which are essential for the anticancer effect of Taxol. Thus, in the stereoselective synthesis of such β-amino-α-hydroxy acids, the literature is described in Tetrahedron Letter ., 35 , pp 2845-2848 (1994), 35 , pp 9289-9292 (1994), J. Org. . Chem ., 59 , pp 1238-1240 (1994), J. Am. Chem. Soc ., 117 , pp 7824-7825 (1995), etc., many studies have been conducted, and the patent is the Republic of Korea Patent Application No. 97-2930. These previous studies mostly relate to the synthesis of pure β- (N-benzoylamino) -α-hydroxy acids.

(Formula B)

On the other hand, in the reaction of the side chain with the hydroxy moiety at the Bacatin III C-13 position in Taxol, the reaction with pure 3- (N-benzoylamino) -2-hydroxy-3-phenylpropionic acid produced in the above synthesis method. Since it requires very vigorous reaction conditions and yields are not good, David et al. ( Tetrahedron Letter , 26 , pp 4483-4484 (1994)) reported that the coupling reaction with oxazoline derivatives is very good. These oxazoline derivatives can characterize steric selectivity and are capable of synthesizing the required single isomers without mixing of the isomers. Therefore, Taxac can be obtained through the process of semi-synthesis with Bacatin III, but it affects the efficacy of Taxol, the final product, depending on how high the synthesis. Therefore, the unique development of the synthesis method of oxazoline, a compound equivalent to various β-amino-α-hydroxy acids, has a very important meaning because it directly affects the purity of Taxol anticancer drugs. It can be of great significance because it can act as an intermediate.

It is an object of the present invention to invent a stereoselective method for synthesizing oxazoline derivatives which are equivalent to β-amino-α-hydroxy acids having high biological activity by using α-amino acids present in various natures as starting materials. Unlike the literature and patents studied so far, the present invention also synthesizes oxazoline derivatives in a unique and novel way to synthesize Taxol of Formula (A) from Bacatin III of Formula (B), as well as to inhibit HIV protease. By providing a material that can be used as an intermediate of the, it is to provide a Taxol synthesis process superior to the methods known so far. Therefore, the present inventors completed a method of stereoselectively synthesizing α-amino acid by carrying out an intramolecular cyclization reaction using palladium (0) as a catalyst. Another object of the present invention is to stereoselectively synthesize oxazoline derivatives used in the coupling reaction with bacatin III in synthesizing taxol to supply taxol to society at a lower price than the synthetic processes produced so far.

Therefore, an object of the present invention is to start the compound of the general formula (II) as a starting material, cyclization reaction at 20 to 50 ℃ in the presence of 0.02 to 0.1 mol% palladium (Pd) catalyst of the general formula (II) compound, The leaving group X was separated to prepare a compound of the following general formula (III), followed by oxidation by adding an oxidizing agent to a mixed solvent of acetonitrile / carbon tetrachloride / water in the presence of a ruthenium (Ru) catalyst to the following general formula (I). It is to provide a method for producing the oxazoline derivative represented.

In the above scheme

R is phenyl, benzyl, methyl, ethyl, isopropyl, isobutyl, cyclohexyl or

Cyclohexylmethyl;

X is acetyl, benzoyl or carbonate as leaving group.

In this case, the palladium (0) catalyst is tetrakistriphenylphosphine palladium (0); Palladium catalyst mixture of Pd (OAc) ₂ , PdCl ₂ and Ph ₃ P; It is characterized in that the catalyst selected from the catalyst mixture of dibenzylidene acetone palladium (0), bridge chlorodiphenyl palladium (0) and hydrazine, the oxidizing agent added to the compound of formula (III) sodium periodate (NaI0 ₄ ), Potassium periodate (KIO ₄ ) and permanganate (KMnO ₄ ) is characterized in that it is selected.

On the other hand, the compound represented by the general formula (II) can be prepared from α-amino acid, and the method for producing the compound of the general formula (I) from the α-amino acid is shown by the following reaction scheme. In the following scheme, R is alkyl, aryl, and specifically phenyl, benzyl, methyl, ethyl, isopropyl, isobutyl, cyclohexyl, cyclohexylmethyl, etc., and the leaving group represented by X is acetyl. , Benzoyl, carbonate and the like, among which acetyl is most preferred.

In the above scheme

X is acetyl, benzoyl or carbonate as leaving group;

Bz represents a benzoyl group; M.C. is methylene chloride;

Ph is phenyl; pyr is pyridine; THF is tetrahydrofuran;

DMSO stands for dimethyl sulfoxide.

Hereinafter, the present invention will be described in more detail.

Although palladium (0) used as a catalyst in the present invention is represented by tetrakistriphenylphosphine palladium (0), Pd (OAc) ₂ , PdCl ₂ and Ph ₃ P may be mixed and used. It is also possible to use dibenzylideneacetone palladium (0), dichlorodiphenyl palladium (0) and hydrazine, but tetrakistriphenylphosphene palladium (0) is most preferred as a catalyst. The amount of palladium (0) can be used in an amount of 0.02 to 0.1 mol%, but 0.04 to 0.06 mol% is most preferable in view of reactivity and economics.

The reaction temperature can be carried out at 20 to 50 ℃ and the most preferred temperature is 22 to 28 ℃. As the reaction solvent, dimethylformamide is most preferred when tetrakistriphenylphosphine palladium (0) is used, and tetrahydrofuran or chloroform is preferably used when dibenzylideneacetone palladium (0) is used. When using palladium (II) acetate and triphenylphosphine, dimethylformamide is most preferred as a solvent. The reaction time is about 6 to 10 hours, and most preferably 7 to 9 hours. As the leaving group represented by X, acetate, benzoyl, and carbonate may be used, but acetate is most preferable in terms of yield and reactivity.

In addition, description of Scheme 2 for synthesizing the compound of the general formula (II) of the starting material of the present invention is as follows.

an α- amino acid (Ⅳ) using NaBH ₄ volume ratio of sulfuric acid of NaBH ₄ in the reduction reaction with the amino alcohol α- (Ⅴ) is about 2: 1 when the sulfuric acid must be added and should be applied just by diluting with ether . When the sulfuric acid is added, the reaction temperature should be between 0 and 20 ° C., and the addition time is preferably 3 to 5 hours, and most preferably 3 to 5 hours for adding 5N-sodium hydroxide to reflux. When the benzoyl chloride is added, the reaction temperature is preferably 0 ° C, and the addition rate is preferably 1.0 to 2.0 ml / min.

In the reaction of oxidizing α-aminoalcohol (V) to α-aminoaldehyde (VI), it is preferable to add solid trioxide / pyridine as a solid, and the reaction temperature is preferably 0 ° C, and the reaction time is between 2 and 3 hours. Is the best yield. The reaction temperature is 20-90 ° C. in the process of producing 4-N-benzoylamino-4-phenyl-2-butynaldehyde using α-aminoaldehyde (VI) with formylmethylenetriphenylphosphorane. Most preferred is 60 ° C. The reaction time is 1.5 to 2.5 hours, and benzene, toluene and chloroform may be used as the solvent. In the reaction for the synthesis of 4-N-benzoylamino-4-phenyl-2-butynol by reducing 4-N-benzoylamino-4-phenyl-2-butynaldehyde, the solvent is tetrahydrofuran / Water (9: 1) is most preferred and the reaction time is about 30 minutes. As for reaction temperature, 0-20 degreeC is preferable.

4-N-benzoylamino-4-phenyl-2-butynol can be converted into a substrate for oxazoline synthesis using palladium (0) using acetic anhydride, benzoyl chloride, ethylchloroformate and the like, respectively. . The reaction time is about 6 to 10 hours, the reaction temperature is preferably 0 ℃ to room temperature. Each amount of acetic anhydride, benzoyl chloride, ethylchloroformate can be used 1.5-2.5 equivalents, but 2.0 equivalents is most preferred.

The present invention describes (S)-(+)-phenylglycine and L-phenylalanine as an example in the following examples, but is not limited thereto and can be applied to all α-amino acids. Include the scope to synthesize I).

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples do not limit the scope of the present invention.

Example 1 Synthesis of Compound of Formula (V)

1 mole (151 g) of S-(+)-phenylglycine was suspended in 1 L of tetrahydrofuran, followed by addition of 2.5 mole (100 g) of NaBH _4, followed by 1.25 mole (66 ml, total volume: 200 ml) diluted in ether at 0 ° C. Was slowly added dropwise. After the dropwise addition of sulfuric acid, the reaction was carried out at room temperature for 12 hours, and then 200 ml of methanol was slowly added, 5 N-NaOH 1L was added, the organic solvent was distilled off and refluxed for 3 hours. After cooling the solution to room temperature, 1 L of methylene chloride was added and 1 mol of benzoyl chloride was slowly added dropwise at 0 ° C. After completion of the reaction, the mixture was filtered under reduced pressure, washed three times with hot water, and dried under reduced pressure to obtain 195 g (81%) of N-benzoylphenylglycineol.

¹ H-NMR (DMSO-d ₆ ) 3.67 (dd, 1H), 4.96 (t, 1H), 5.06 (dd, 1H), 7.20-7.55 (m, 8H), 7.90 (m, 2H), 8.72 (d , 1H)

Example 2 Synthesis of Compound of General Formula (VI)

0.1 mole (24.1 g) of N-benzoylphenylglycineol was suspended in 100 ml of methylene chloride / methyl sulfoxide 5: 1 solvent, cooled to 0 ° C., and 31.8 g (0.2 mole) of sulfur trioxide-pyridine was added thereto, followed by triethylamine. 55 ml (0.4 mol) was added and stirred for 2 hours. After the reaction was completed, 200 ml of ethyl acetate was added, washed with 100 ml of water and 100 ml of saturated NH ₄ Cl solution, dried over anhydrous magnesium sulfate, filtered and dried to obtain 21 g (87%) of crude N-benzoylaminoaldehyde. Used without purification.

¹ H-NMR (CDCl ₃ ) 4.80 (br, 1H), 6.19 (d, 1H), 7.23-7.87 (m, 10H), 9.83 (s, 1H)

Example 3 Synthesis of Compound of Formula (VII)

Toluene 100 ml was added to 21 g (0.087 mol) of N-benzoylphenyl glycine aldehyde, and 34 g (0.11 mol) of formylmethylene triphenylphosphorane were added and refluxed for 2 hours. After the reaction was completed, the mixture was dried under a reduced pressure and separated by column chromatography (nucleic acid: ethyl acetate = 1: 1) to obtain 13.8 g (60%) of 4-N-benzoylamino-4-phenyl-2-butynaldehyde.

Example 4 Synthesis of Compound of Formula (IX)

To 13.3 g (0.05 mol) of 4-N-benzoylamino-4-phenyl-2-butynaldehyde, 50 ml of tetrahydrofuran / water (9: 1) was added and 1.9 g (0.05 mol) of NaBH ₄ were added. After stirring for 30 minutes, 30 ml of 1N-HCl was added, extracted with 50 ml of ether, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 13.6 g of crude 4-N-benzoylamino-4-phenyl-2-butynol. Used for.

Example 5 Synthesis of Compound of Formula (II)

20 ml of pyridine was added to 13.6 g (0.05 mol) of 4-N-benzoylamino-4-phenyl-2-butynol, and 10.2 g (0.1 mol) of acetic anhydride were added and stirred for 4 hours. After completion of the reaction, 50 ml of methylene chloride was added, washed with 50 ml of 1N-HCl and 50 ml of saturated NaHCO ₃ solution, and then recrystallized with a nucleic acid: ethyl acetate (2: 1) solvent to give 14.7 g (95%) of 1-acetoxy-4. -N-benzoylamino-4-phenyl-2-butyne was synthesized.

¹ H-NMR (CDCl ₃ ) 2.08 (s, 3H), 4.63 (d, 2H), 5.82 (dt, 1H), 5.89 (dd, 1H), 6.04 (dd, 1H), 6.4 (br, 1H), 7.32-7.53 (m, 8H), 7.79 (m, 2H)

Other leaving groups can also be synthesized using benzoyl chloride and methylchloroformate in the same manner as described above.

Example 6 Synthesis of Compound of Formula (V)

After 1 mole (163 g) of L-phenylalanine was suspended in 1 L of tetrahydrofuran, 2.5 mole (100 g) of NaBH ₄ was added thereto, and then 1.25 mole (66 m, total volume: 200 ml) of sulfuric acid diluted in ether at 0 ° C. was slowly added dropwise. After the dropwise addition of sulfuric acid, the reaction was carried out at room temperature for 12 hours, and then 200 ml of methanol was slowly added thereto, and 5 N-NaOH 1 L was added thereto, followed by distillation of the organic solvent and refluxing for 3 hours. After cooling the solution to room temperature, 1 L of methylene chloride was added and 1 mol of benzoyl chloride was slowly added dropwise at 0 ° C. After completion of the reaction, the resultant was filtered under reduced pressure, washed three times with hot water and dried under reduced pressure to obtain 207 g (81%) of N-benzoylphenylalaninol.

¹ H-NMR (DMSO-d ₆ ) δ2.79 (dd, 1H), 2.94 (dd, 1H), 3.45 (m, 2H), 4.14 (m, 1H), 4.87 (bt, 1H), 7.13-7.51 (m, 8H), 7.77 (d, 2H), 8.18 (d, 1H)

Example 7 Synthesis of Compound of General Formula (VI)

0.1 mole (25.5 g) of N-benzoylphenylalanineol was suspended in 100 ml of methylene chloride / methyl sulfoxide 5: 1 solvent, cooled to 0 ° C., and 31.8 g (0.2 mole) of sulfur trioxide-pyridine was added thereto, followed by triethyl. 55 ml (0.4 mol) of lamin was added, followed by stirring for 2 hours. After completion of the reaction, 200 ml of ethyl acetate was added, washed with 100 ml of water and 100 ml of saturated NH4Cl solution, dried over anhydrous magnesium sulfate, filtered and dried to give 22 g (87%) of crude N-benzoylaminoaldehyde. Used.

¹ H-NMR (CDCl ₃ ) δ3.32 (m, 2H), 4.93 (dd, 1H), 6.71 (m, 1H), 7.20-7.72 (m, 8H), 7.74 (d, 2H), 9.74 (s , 1H)

Example 8 Synthesis of Compound of Formula (VII)

Toluene 100ml was added to 22g (0.087mol) of N-benzoylphenylalanine aldehyde, 34g (0.11mol) of formylmethylene triphenylphosphorane was added, and it heated and refluxed for 2 hours. After completion of the reaction, the reaction mixture was dried under reduced pressure and separated by column chromatography (nucleic acid: ethyl acetate = 1: 1) to obtain 14.6 g (60%) of 4-N-benzoylamino-5-phenyl-2-pentenal.

¹ H-NMR (CDCl ₃ ) δ3.12 (m, 2H), 5.22 (m, 1H), 6.20 (dd, 1H), 6.83 (dd, 1H), 7.20-7.77 (m, 10H), 9.49 (d , 1H)

Example 9 Synthesis of Compound of Formula (IX)

To 14.0 g (0.05 mol) of 4-N-benzoylamino-5-phenyl-2-pentenal was added 50 ml of tetrahydrofuran / water (9: 1) and 1.9 g (0.05 mol) of NaBH ₄ were added. After stirring for 30 minutes, 30 ml of 1N-HCl was added, extracted with 50 ml of ether, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain 14.06 g of crude 4-N-benzoylamino-5-phenyl-2-pentenol. Used.

Example 10 Synthesis of Compound of Formula (II)

20 ml of pyridine was added to 14.6 g (0.05 mol) of 4-N-benzoylamino-5-phenyl-2-pentenol, and 10.2 g (0.1 mol) of acetic anhydride was added thereto, followed by stirring for 4 hours. After completion of the reaction, 50 ml of methylene chloride was added, washed with 50 ml of 1N-HCl, 50 ml of saturated NaHCO ₃ solution, and recrystallized with a nucleic acid / ethyl acetate (2: 1) solvent to give 15.36 g (95%) of 1-acetoxy-4. -N-benzoylamino-5-phenyl-2-pentene was synthesized.

¹ H-NMRδ2.05 (s, 3H), 3.00 (dd, 2H), 4.54 (d, 2H), 5.02 (m, 1H), 5.70 (dt, 1H), 5.84 (dd, 1H), 7.22-7.49 (m, 8H), 7.67-7.69 (m, 2H)

Other leaving groups were also synthesized using benzoyl chloride and methylchloroformate in the same manner as described above.

Example 11 Synthesis of Compound of General Formula (III)

15.6 mg (0.65 mmol) sodium hydride was suspended in 2 ml of dimethylformamide (hereinafter referred to as DMF), followed by 200 mg (0.65 mmol) of 1-acetoxy-4-N-benzoylamino-4-phenyl-2-butyne. It was dissolved in 1 ml of DMF and slowly added dropwise at 0 ° C, and 38.1 mg (0.033 mmol) of tetrakistriphenylphosphine palladium (0) was added. After stirring for 8 hours, the reaction was completed and 20 ml of ethyl acetate was added, washed 5 times with 4 ml of distilled water and once with 20 ml of brine, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, followed by column chromatography (nucleic acid: Ethyl acetate = 6: 1) afforded 84.3 mg (52%, 100% de) of (4S-trans) -4,5-dihydro-2,4-diphenyl-5-vinyl-oxazoline.

¹ H-NMR (CDCl ₃ ) 4.88 (dd, J = 7.0, 8.0 Hz, 1H), 5.05 (d, J = 8.0 Hz, 1H), 5.33 (d, J = 10.5 Hz, 1H), 5.38 (d, J = 17.5 Hz, 1H), 6.09 (ddd, J = 7.0, 10.5, 17.5 Hz, 1H), 7.31-7.53 (m, 8H), 8.08 (m, 2H)

Example 12 Synthesis of Compound of General Formula (III)

15 mg (0.61 mmol) of sodium hydride was suspended in 2 ml of DMF, and then 200 mg (0.61 mmol) of 1-acetoxy-4-N-benzoylamino-5-phenyl-2-pentene was dissolved in 1 ml of DMF and slowly added dropwise at 0 ° C. 36 mg (0.03 mmol) of tetrakistriphenylphosphine palladium was added thereto. After stirring for 8 hours, the reaction was completed and 20 ml of ethyl acetate was added, washed 5 times with 4 ml of distilled water and once with 20 ml of brine, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure, followed by column chromatography (nucleic acid: Ethyl acetate = 4: 1) afforded 79 mg (53% yield, 60% de) of (4S-trans) -4,5-dihydro-2-phenyl-4-benzyl-5-vinyl-oxazoline .

¹ H-NMR δ 2.79 (dd, J = 7.5, 13 Hz, 1H), 3.26 (dd, J = 5.5, 13 Hz, 1H), 4.26 (ddd, J = 5.5, 7.0, 7.5 Hz, 1H), 4.76 ( dd, J = 6.5, 7.0 Hz, 1H), 5.06 (dd, 2H), 5.72 (ddd, 1H), 7.22-7.51 (m, 8H), 7.97-8.01 (m, 2H)

Example 13 Synthesis of Compound of General Formula (III)

15.6 mg (0.65 mmol) of sodium hydride is suspended in 2 ml of DMF, and then 200 mg (0.65 mmol) of 1-acetoxy-4-N-benzoylamino-6-methyl-2-heptin is dissolved in 1 ml of DMF and slowly added at 0 ° C. 38.1 mg (0.033 mmol) of tetrakistriphenylphosphine palladium (0) was added dropwise. After stirring for 8 hours, after completion of the reaction, 20 ml of ethyl acetate was added, washed 5 times with 4 ml of distilled water and once with 20 ml of brine, dried over magnesium sulfate, filtered, and distilled under reduced pressure, followed by column chromatography (nucleic acid: ethyl). Acetate = 6: 1) to separate 84.3 mg (61% yield, 58% de) of (4S-trans) -4,5-dihydro-2-phenyl-4-isopropyl-5-vinyl-oxazoline Got it.

The yield of intramolecular cyclization reaction catalyzed by palladium (0) for various R groups and leaving groups is summarized in Table 1.

Leaving machine (X) Acetyl Benzoyl Methyl carbonate R Phenyl 52% 35% 37% benzyl 53% 37% 39% Isopropyl 61% 39% 43%

Example 14 Synthesis of Compound of Formula (I)

124.6 mg of (4S-trans) -4,5-dihydro-2,4-diphenyl-5-vinyl-oxazoline in 10 ml of acetonitrile / carbon tetrachloride / water (1: 1: 1) mixed solution stirred at room temperature After adding (0.5 mmol), 273 mg (3.25 mmol) of sodium bicarbonate and 588 mg (5.75 mmol) of sodium periodate were added thereto, stirred for 5 minutes, and then a catalytic amount of ruthenium chloride (about 1 mg) was added thereto, followed by stirring for 2 days. After completion of the reaction, the mixture was extracted with ether, acidified with 1N-HCl, and extracted with methylene chloride (4S-trans) -4,5-dihydro-2,4-diphenyl-5-carboxylic acid 105.5 mg (53% yield). , 100% de) was obtained. 10 ml of ether was added to the compound, diazomethane was added for methyl esterification, and the ether was distilled under reduced pressure to give 110 mg of (4S-trans) -4,5-dihydro-2,4-diphenyl-5-carboxylic acid methyl ester. Got it.

¹ H-NMR (CDCl ₃ ) 3.84 (s, 3H), 4.91 (d, J = 6.5 Hz, 1H), 5.45 (d, J = 6.5 Hz, 1H), 7.29-7.57 (m, 8H), 8.08 ( m, 2H)

Example 15 Synthesis of Compound of Formula (I)

(4S-trans) -4,5-dihydro-2-phenyl-4-benzyl-5-vinyl-oxazoline in 10 ml of acetonitrile / carbon tetrachloride / water (1: 1: 1) mixed solution stirred at room temperature. After adding mg (0.5 mmol), 273 mg (3.25 mmol) of sodium bicarbonate and 588 mg (5.75 mmol) of sodium periodate were added and stirred for 5 minutes, followed by adding a catalytic amount of ruthenium chloride (about 1 mg) and stirring for 2 days. After completion of the reaction, the mixture was extracted with ether, acidified with 1N-HCl, extracted with methylene chloride, and 95.6 mg (68% yield) of (4S-trans) -4,5-dihydro-2-phenyl-4-benzyl- 5-carboxylic acid was obtained.

The present invention has the advantage that it can be applied to all the various α-amino acids compared to the existing method, in particular 3- (N-benzoylamino) -2-hydroxy-3-phenylpropionic acid which is a component of the taxol side chain When synthesizing the equivalent oxazoline derivative (I), only one stereoisomer can be selectively synthesized. Thus, as an efficient method for synthesizing a taxol side chain, taxol can be synthesized with higher purity than conventional methods. In addition, since the above-mentioned disadvantages of 3- (N-benzoylamino) -2-hydroxy-3-phenylpropionic acid can be solved in the synthesis of taxol, it has an advantage that it is very economical than conventional methods in the synthesis of taxol. . Furthermore, it is a comprehensive compound capable of synthesizing intermediates of HIV protease inhibitors using the oxazoline derivative (I) of the present invention and its use is very high.

Claims (4)

Using the compound of the following general formula (II) as a starting material, cyclization reaction is carried out at 20 to 50 ° C. in the presence of 0.02 to 0.1 mol% of a palladium (Pd) catalyst of the general formula (II) compound, and the leaving group X is released. A compound of the following general formula (III) was prepared, and an oxidizing agent was added to a mixed solvent of acetonitrile / carbon tetrachloride / water in the presence of a ruthenium (Ru) catalyst to oxidize and react with the oxazoline derivative represented by the following general formula (I). Manufacturing method (Scheme 1) In the above scheme R is phenyl, benzyl, methyl, ethyl, isopropyl, isobutyl, cyclohexyl or Cyclohexylmethyl; X is acetyl, benzoyl or carbonate as leaving group. The method of claim 1, wherein the palladium (0) catalyst is tetrakistriphenylphosphine palladium (0); Palladium catalyst mixture of Pd (OAc) ₂ , PdCl ₂ and Ph ₃ P; Method for producing an oxazoline derivative characterized in that the catalyst selected from the catalyst mixture of dibenzylidene acetone palladium (0), dichlorodiphenyl palladium (0) and hydrazine The preparation of an oxazoline derivative according to claim 1, wherein the oxidizing agent added to the compound of the general formula (III) is selected from sodium periodate (NaIO ₄ ), potassium periodate (KIO ₄ ), and potassium permanganate (KMnO ₄ ). Way The method for preparing an oxazoline derivative according to claim 1, wherein the synthesis of the compound of general formula (II) is synthesized using the amino acid as a starting material. (Scheme) In the above scheme X is acetyl, benzoyl or carbonate as leaving group; Bz represents a benzoyl group; M.C. is methylene chloride; Ph is phenyl; pyr is pyridine; THF is tetrahydrofuran; DMSO stands for dimethyl sulfoxide.